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Association of Crohn’s disease and ulcerative colitis with the risk of neurological diseases: a large-scale Mendelian randomization study

Journal of Human Genetics (2024)Cite this article

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Abstract

Observational studies suggested increased risks of Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) in patients with Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01–1.05; P = 1.80 × 10−3) and MS (combined: OR, 1.37; 95% CI, 1.23–1.53; P = 1.18 × 10−8), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.

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Acknowledgements

We thank the authors and participants of all GWASs used, for making their results publicly available. We also acknowledge the participants and investigators of the FinnGen study. Full acknowledgement and funding statements for each of these resources are available via the relevant cited reports.

Funding

This study was supported by the National Natural Science Foundation of China (grant: 82103921 and 82020108028) and the Natural Science Research Project of Jiangsu Provincial Higher Education (grant: 21KJB330006).

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  1. These authors contributed equally: Yinan Wang, Yiming Jia.

Authors and Affiliations

  1. Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Major Chronic Non-communicable Diseases, Suzhou Medical College of Soochow University, Suzhou, China

    Yinan Wang, Yiming Jia, Qingyun Xu, Pinni Yang, Lulu Sun, Yi Liu, Xinyue Chang, Yu He, Mengyao Shi, Daoxia Guo, Yonghong Zhang & Zhengbao Zhu

  2. Ningbo Center for Disease Control and Prevention, Ningbo, China

    Yinan Wang

  3. School of Nursing, Suzhou Medical College of Soochow University, Suzhou, China

    Daoxia Guo

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Wang, Y., Jia, Y., Xu, Q. et al. Association of Crohn’s disease and ulcerative colitis with the risk of neurological diseases: a large-scale Mendelian randomization study. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01271-4

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